Docking Simulations Research Articles

Anti-Cancer Activity, DFT and molecular docking study of new BisThiazolidine amide

In this study, a series of bis amide thiazolidine derivatives (Q1-Q6) were synthesized and their anticancer activity was evaluated against prostate (PC3) and breast (MCF7) cancer cells and normal cells line activity was evaluated against breast (MCF10), prostate (PNT1A) and living human cells (HUVEC) cancer cells. The thiazolidine rings were built from penicillamine and aromatic aldehydes (A1-A6), then converted to acetyl thiazolidines (B1-B6) using acetic anhydride, and finally linked with phenylene diamine to form the final compounds (Q1-Q6). Notably, compounds Q1 and Q3 displayed the highest activity against PC3, with IC50 values of 81 and 89 µg/ml, respectively. Docking simulations were performed for Q1, Q4, and Q5 against protein structures related to cancer (2FVD and 1SJ0). Additionally, DFT calculations were used to determine various molecular properties like HOMO/LUMO energies, band gap, and other descriptors, providing insights into the compounds’ stability and reactivity.

Integrating computational methods and in vitro experimental validation reveals the pharmacological mechanism of Selaginella bryopteris (L.) Baker targeting major proteins in breast cancer

Breast cancer remains a significant global health challenge, necessitating the exploration of novel therapeutic options. The present study employs an integrated approach encompassing network pharmacology, molecular docking, molecular dynamics simulations, and in-vitro validation to investigate the potential of Selaginella bryopteris in breast cancer treatment. Initial network pharmacology analysis revealed different potential targets and pathways associated with breast cancer that could be modulated by S. bryopteris phytochemical constituents. Molecular docking and dynamics simulations further elucidated the stability and dynamics of protein-ligand complexes (lanaroflavone–EGFR and sequoiaflavone-CTNNB1). The in-vitro assays demonstrated the ability of S. bryopteris crude extract to inhibit cancer cell growth (IC50 - 78.34 μg/mL) migration and invasion, supporting the computational predictions. The integrated approach employed in the present study offers a robust framework for the systematic exploration of S. bryopteris in drug discovery as a promising candidate for breast cancer treatment.

High-Speed Countercurrent Chromatography Isolation of Active Components from Evodia Rutaecarpa and Affinity Ultrafiltration Screening for Their Acetylcholinesterase Inhibitor Activity.

Acetylcholinesterase inhibitors from Evodia rutaecarpa were screened, prepared, and evaluated. To screen the lipophilic alkaloid active constituents in E. rutaecarpa, we improved and optimized an ultrafiltration system. Three acetylcholinesterase (AChE) inhibitors, dehydroevodiamine, evodiamine, and rutecarpine, were screened. Addressing the limitations of the traditional response surface methodology (RSM) for multiobjective screening, we integrated RSM with the Non-dominated Sorting Genetic Algorithm III to achieve the optimal extraction of these active ingredients. High-speed countercurrent chromatography was used to isolate the active components using a two-phase solvent system: n-hexane/ethyl acetate/methanol/water (3.0:2.5:3.5:2.0, v/v/v/v) and ethyl acetate/methanol/water (3.0:1.0:4.0, v/v/v). The nuclear magnetic resonance spectroscopy confirmed the structures of the compounds, and molecular docking and dynamics simulations assessed the inhibitory effects of the chemical components on AChE, which were consistent with the findings of the ultrafiltration experiments. We also confirmed the neuroprotective properties of these compounds against glutamate-induced apoptosis in PC12 cells. Overall, we achieved the systematic optimization of multitarget compound extraction and lipophilic alkaloid ultrafiltration screening, as well as preparation and activity validation, laying the groundwork for the development of AChE inhibitors from lipophilic alkaloids.

Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.

Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected invitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.

Qisheng wan decoction alleviates the inflammation of CCI rats via TRP channels

Qisheng wan decoction (QWD), a traditional Chinese medicine, has promising potential anti-inflammatory effects against neuropathic pain (NP). However, its valid ingredients and specific anti-inflammatory mechanisms are still unclear. This study aimed to identify the active ingredients of QWD responsible for its anti- inflammatory effect by combining liquid chromatography with network pharmacology, and to explore its anti- inflammatory mechanism by chronic constriction injury (CCI) model rats. The UHPLC-Q Exactive Orbitrap-MS technique was used to identify the active ingredients of QWD. The potential ingredients of QWD, which targeted to the pathways of treating NP, were performed by network pharmacology, molecular docking and molecular dynamics simulations. After CCI rats-induced NP model operation, QWD (5.6 g/kg/d, 11.2 g/kg/d, 22.4 g/kg/d) and Pregabalin (10g/kg/d) as positive controls, were administered to the rats for 7 days. The behaviors of the different groups were tested at 0, 1, 3, 5, 7, 12 days, respectively. And the inflammatory factor including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) was detected by ELISA. Meantime, the inflammation of the sciatic nerve was evaluated by the hematoxylin-eosin staining. Ionized calcium-binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) were detected by immunohistochemistry. Moreover, the expressions of TRPA1, TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and P38 mitogen-activated protein kinase (MAPK) were tested by RT-PCR, western blot, and immunohistochemistry. After screening by the liquid chromatography and network pharmacology approach, seventy ingredients of QWD were identified, and seven core targets including oncogene tyrosine-protein kinase (SRC), mitogen-activated protein kinase 3 (MAPK3), signal transducer and activator of transcription 1 (STAT1), protein-serine-threonine kinase 1 (AKT1), mitogen-activated protein kinase 1 (MAPK1), TNF-α, and IL-6 were confirmed. Six active ingredients exhibited binding energies less than -5 kcal/mol, and the complexes were structurally stable within 50 ns. Pathway analysis indicated that transient receptor potential (TRP) channels were mainly responsible for anti-inflammatory mediator regulation. Compared with the CCI group, the behavioral tests showed that QWD-L, QWD-M, and QWD-H group alleviated mechanical, thermal and cold hyperalgesia (p<0.05). HE staining results found out QWD-L, QWD-M, and QWD-H group decreased the inflammation of the sciatic nerve (p<0.05). Similarly, compared with the CCI group, the serum level of TNF-α and IL-6 of QWD groups decreased conformably (p<0.05). This reduction was downtrend with the inhibition of Iba-1, GFAP, and the TRP channel signaling pathway and p38 MAPK. This study provides a primary investigation of the composition of QWD for its anti- inflammation effect and its molecular mechanism in CCI model rats. And this therapeutic efficacy of QWD was achieved by decreasing the inflammation. QWD also inhibited the level TNF-α and IL-6 and decreasing the activation of Iba-1 and GFAP in glia. And this anti-inflammation mechanism involved in inhibiting the TRPA1, TRPV1, TRPV2, TRPV4, and TRPM8 and p38 MAPK signaling pathways. These findings provide a scientific and theoretical basis for the prevention and treatment of NP with QWD.

Molecular Docking and Molecular Dynamics Simulations of the Urease Inhibitory Activity of 2,3‐Dihydroxybenzohydrazide Derivatives

AbstractThis investigation focuses on a suite of 2,3‐dihydroxybenzoyl hydrazine derivative ligands, examining their viability as urease activity inhibitors and delving into their operative mechanisms. Utilizing molecular docking approaches, the binding patterns and interactive loci of 2,3‐dihydroxybenzoyl hydrazine derivatives with urease were elucidated. The origin of the binding forces between the ligands and urease, along with pertinent descriptors, were scrutinized through an amalgamation of density functional theory calculations and molecular dynamics simulations. The findings indicate that the HOMO‐LUMO energy gap, the dipole moment, and the electrostatic potential serve as robust descriptors of the inhibitory activity exhibited by 2,3‐dihydroxybenzoyl hydrazine derivative ligands against urease. The ligand designated BH‐k emerged as the most efficacious urease inhibitor, with critical hydrogen bonds forming between it and the residues His409, Ala636, and Asp633, in addition to hydrophobic interactions with Arg439. The design of ligands capable of establishing additional hydrogen bonds constitutes an effective strategy to amplify inhibitory efficacy. The results of this research aspire to lay a theoretical foundation for the advancement of novel urease inhibitor designs to counteract health issues emanating from aberrant urease activity.

Clarifying therapeutic mechanisms of Guanxinshutong capsule for cardiac fibrosis treatment by network pharmacology, molecular docking, molecular dynamics simulation, and in vivo experiments

PurposeGuanxinshutong capsule (GXST) is a Chinese patent medicine used for the treatment of cardiac fibrosis (CF). Nevertheless, the precise mechanism of action of GXST remains unclear. In this study, we applied network pharmacology, molecular docking, molecular dynamics simulation, and in vivo experiments to assess the effects and mechanisms of GXST in the treatment of CF. MethodsThe TCMSP database provided the GXST targets and active substances. The GeneCards, OMIM, and TTD databases were searched for targets relevant to cardiac fibrosis. To filter core targets, a PPI network was set up. Metascape was utilized to conduct enrichment analysis for the KEGG and GO pathways. To evaluate the interaction between putative targets and active drugs, molecular docking was utilized. MDS was performed for the optimal complex of the core ligand protein identified through molecular docking. Induction of cardiac fibrosis in SD rats using isoproterenol, and the protective effects of GXST on the heart were evaluated using echocardiography, H&E staining, and Masson staining. ResultsThrough network pharmacology analysis, we have identified 83 active components and 73 key target proteins related to cardiac fibrosis from GXST. Subsequent molecular docking and molecular dynamics simulation results suggest that quercetin, luteolin, and kaempferol can inhibit cardiac fibrosis by regulating the expression of TNF-α, IL6, and IL1B proteins. These compounds and proteins may be key factors in the treatment of CF with GXST. Further, in vivo experiments demonstrate that GXST can alleviate myocardial injury and improve cardiac function in CF rats. ConclusionThis study successfully predicted the effective components, potential targets, and related pathways involved in treating CF by GXST. GXST can improve cardiac function and alleviate pathological damage in the hearts of SD rats. This provides a new strategy for future investigations into the mechanisms of GXST in the treatment of CF.

Exploration of Pharmacological Mechanism of Cinnamomum tamala Essential Oil in Treating Inflammation based on Network Pharmacology, Molecular Modelling, and Experimental Validation.

Cinnamomum tamala (Buch.-Ham.) T.Nees & Eberm., also known as Indian Bay leaf, holds a distinctive position in complementary and alternative medicinal systems due to its anti-inflammatory properties. However, the active constituents and key molecular targets by which C. tamala essential oil (CTEO) exerts its anti-inflammatory action remain unclear. The present study used network pharmacology and experimental validation to investigate the mechanism of CTEO in the treatment of inflammation. GC-MS analysis was used to identify the constituents of CTEO. The key constituents and core targets of CTEO against inflammation were obtained by network pharmacology. The binding mechanism between the active compounds and inflammatory genes was ascertained by molecular docking and molecular dynamics simulation analysis. The pharmacological mechanism predicted by network pharmacology was verified in lipopolysaccharide-stimulated murine macrophage (RAW 264.7) cell lines. Forty-nine constituents were identified by GC-MS analysis, with 44 constituents being drug-like candidates. A total of 549 compounds and 213 inflammation-related genes were obtained, revealing 68 overlapping genes between them. Compound target network analysis revealed cinnamaldehyde as the core bioactive compound with the highest degree score. PPI network analysis demonstrated Il-1β, TNF-α, IL8, IL6 and TLR4 as key hub anti-inflammatory targets. KEGG enrichment analysis revealed a Toll-like receptor signalling pathway as the principally regulated pathway associated with inflammation. A molecular docking study showed that cinnamaldehyde strongly interacted with the Il-1β, TNF-α and TLR-4 proteins. Molecular dynamics simulations and MMPBSA analysis revealed that these complexes are stable without much deviation and have better free energy values. In cellular experiments, CTEO showed no cytotoxic effects on RAW 264.7 murine macrophages. The cells treated with LPS exhibited significant reductions in NO, PGE2, IL-6, TNF-α, and IL-1β levels following treatment with CTEO. Additionally, CTEO treatment reduced the ROS levels and increased the antioxidant enzymes such as SOD, GSH, GPx and CAT. Immunofluorescence analysis revealed that CTEO inhibited LPS-stimulated NF-κB nuclear translocation. The mRNA expression of TLR4, MyD88 and TRAF6 in the CTEO group decreased significantly compared to the LPS-treated group. The current findings suggest that CTEO attenuates inflammation by regulating TLR4/MyD88/NF- κB signalling pathway.

Investigating Sortase A inhibitory potential of herbal compounds using integrated computational and biochemical approaches

Multi-drug resistance in bacteria is emerging as a major global health challenge, causing substantial harm in terms of mortality, morbidity, and financial strain on healthcare systems. These bacteria are constantly acquiring new virulence factors and drug-resistance mechanisms, which highlights the critical need for innovative antimicrobial medicines and identification of new therapeutic targets, such as Sortase A (EfSrtAΔN59). EfSrtAΔN59, a transpeptidase significant for the adhesion and virulence of Enterococcus faecalis (E. faecalis), presents an attractive target for disrupting biofilm formation—a key factor in persistent infections. This study investigates the inhibitory effects of two natural flavonoids- Rutin Trihydrate and Quercetin, on EfSrtAΔN59 and biofilm formation in E. faecalis. With in vitro enzymatic assays and biofilm quantification techniques, we demonstrate that both compounds significantly attenuate EfSrtAΔN59 activity, thereby hindering bacterial biofilm formation. Rutin Trihydrate and Quercetin exhibited strong binding affinities to the EfSrtAΔN59 enzyme, as confirmed by molecular docking and MD simulation studies. This was further substantiated by a notable reduction in biofilm biomass in bacterial cultures treated with these compounds. These findings highlight the potential of Rutin Trihydrate and Quercetin as promising candidates for the development of novel anti-virulence therapies aimed at mitigating E. faecalis infections, thereby offering a compelling alternative to traditional antibiotics.

Activity-based protein profiling guided new target identification of quinazoline derivatives for expediting bactericide discovery: Activity-based protein profiling derived new target discovery of antibacterial quinazolines

IntroductionThe looming antibiotic-resistance problem has imposed an enormous crisis on global public health and agricultural development. Even worse, the evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens have made the resurgence of diseases that were once easily treatable deadly again. The development of antibiotics with novel mechanisms of action is urgently required. ObjectivesInspired by charming activity-based protein profiling (ABPP) technology and increasing attention to quinazolines in the development of antibacterial agents, this study engineered a series of new quinazoline derivatives, assessed their antibacterial profiles, and first identified the possible target. MethodsThe target identification and their possible binding sites were verified by ABPP technology, molecular docking, and molecular dynamic simulations. The fatty acid synthesis process was analyzed by gas chromatography, propidium iodide staining, and scanning electron microscopy. The physicochemical properties and fungicide-likeness were evaluated using the Fungicide Physicochemical-properties Analysis Database. ResultsCompound 7a, an acrylamide-functionalized quinazoline derivative, exhibited excellent antibacterial potency against Xanthomonas oryzae pv. oryzae with an EC50 value of 13.20 µM. More importantly, ABPP technology showed that β-ketoacyl-ACP-synthase Ⅱ (FabF) was the first identified quinazolines’ potential target. Compound 7a could selectively bind to the Cys151 residue of FabF through covalent interaction, suppress fatty acid biosynthesis, and damage the cell membrane integrity, thereby killing the bacteria. The pot experiment results showed that compound 7a demonstrated protective and curative values of 49.55 % and 47.46 %, surpassing controls bismerthiazol and thiodiazole copper. Finally, compound 7a exhibited low toxicity towards non-target organisms. These unprecedented performances contributed to excavating new quinazoline-based bactericidal agents. ConclusionOur research highlights the superiority of ABPP technology, for the first time, identifies the target of engineered quinazolines in pathogenic bacteria, and their potential target fished by ABPP tools holds great promise for the development of quinazoline-based and/or FabF-targeted bactericides.

New quinoxaline-oxadiazole hybrids as tubulin inhibitors: Synthesis, cytotoxicity, and molecular dynamics simulations

This study describes the synthesis and biological evaluation of a series of novel quinoxaline-oxadiazole hybrid compounds. These compounds were designed to enhance anticancer activity through the incorporation of specific pharmacophoric groups. Structural characterization using NMR and HRMS spectroscopy confirmed the successful synthesis of the hybrids. Cytotoxicity assays revealed that several compounds exhibited significant activity against various cancer cell lines. Compounds 8a and 8f demonstrated potent activity against A549 cells, while 8a, 8b, and 8c were effective against HaCaT cells. Additionally, compounds 8i and 8a showed activity against HepG2 cells. Molecular docking and dynamics simulations suggested that compounds 8c and 8d bind strongly to the tubulin protein, a target for anticancer drugs. These compounds exhibited binding affinities comparable to known anticancer compounds. The results of this study highlight the potential of quinoxaline-oxadiazole hybrids, especially those with halogen substitutions, as promising candidates for the development of novel anticancer therapeutics.

Pongamia pinnata L. seed-derived karanjin as prominent antiviral agent against Newcastle disease virus

Current study aim to explore Karanjin (Kar) isolated from the seeds of Pongamia pinnata as a potential antiviral polyphenol against Newcastle disease virus (NDV) through comprehensive investigations. For the in vitro study, plaque assays, gene and protein expression were used to analyse the inhibitory impact of Kar on NDV, where it reduced NDV replication as shown by a 13-fold suppression of the hemagglutinin-neuraminidase (HN) gene and decrease about 60% in virus activity. In ovo study showed that Kar mitigates NDV effects in chicken embryos. In silico studies involving molecular docking and molecular dynamics simulations showed strong binding between Kar and HN protein of NDV. Kar also influenced glucose metabolism, enhancing antiviral responses, as showed by the upregulation of GLUT1 and HEX genes through RT-qPCR and HPLC analyses. The study contributes valuable insights for future investigations into therapeutic applications of Kar against viral infections.

Multifaceted Analysis of Bempedoic Acid Binding to Subdomain IIA of Human Serum Albumin

The molecular association between bempedoic acid (BAC) and the major blood plasma transporter, human serum albumin (HSA), was investigated using molecular docking, molecular dynamics (MD) simulation, isothermal titration calorimetry (ITC), atomic force microscopy (AFM), and spectroscopic techniques. During the docking and MD simulation investigations, it was observed that BAC interacted with subdomain IIA (Site I) of HSA through hydrogen bonds and hydrophobic interactions. This interaction ensured the stability of the complex throughout the duration of 100 ns. The observed enhancement in the fluorescence intensity of HSA after BAC inclusion and the swelling of HSA generated by BAC in the AFM data also suggested the formation of a complex between BAC and HSA. The BAC demonstrated a moderate affinity towards HSA, with a binding constant (Ka) of 1.21 ± 0.05 × 105 M−1 at 300 K. Notable modifications in the secondary and tertiary structures of the protein, as well as changes in the protein's Tyr/Trp surroundings, were observed using circular dichroism and three-dimensional fluorescence spectra when the protein was attached to BAC. Insightful information regarding molecular interactions that regulate the stability of the BAC-HSA complex is provided by these investigations.

Virtual screening-led design of inhibitor scaffolds for the NLRP3 inflammasome

The NLRP3 inflammasome is a key target for drug discovery due to its implication in a range of inflammation-related diseases. In this work, we identify new inhibitors of the NLRP3 inflammasome via a hierarchical virtual screening strategy using molecular similarity, docking and MD simulation. The most potent inhibitors identified from a subsequent biological assay (IC50 of 1 – 4 μM) feature a sulfonamide group, a motif known to favour NLRP3 inhibition, in conjunction with an indole, benzofuran or tricyclic 6,7-dihydro-5H-indeno[5,6-b]furan ring, yielding novel scaffolds. These structures provide a basis for the design of more potent, selective NLRP3 inhibitors.

Structure, function and stability analysis on potential deleterious mutation ensemble in glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for early detection of LUAD

AimsLung adenocarcinoma (LUAD) is the most prominent histological subtype among the lung cancer which is a leading cause in the cancer mortality rate. High mutational and glycolytic rates are the major reported alterations in the lung cancer. Here in our study we are elucidating the structural and functional role of key glycolytic enzyme Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and associated SNPs in LUAD progression. Materials and methodsOur gene expression analysis reveals high expression of GAPDH in the LUAD. In silico tools and analysis were used for the identification and characterization of the deleterious SNPs. Molecular Docking and dynamics simulations (MDS) studies characterized the structural consequences of prioritized deleterious mutations. Key findingsThe sequence based analysis to identify SNPs in GAPDH resulted in 28 deleterious SNPs and 6 SNPs among them showed deleterious and damaging effect. The structural based analysis resulted in 2 stabilizing SNPs of rs ids rs11549328 (D39Y) and rs200102749 (S51Y) in the conserved domain. The IDR and PTM analysis of the GAPDH sequence resulted an IDR region from 191 to 194 positions with an IDR score of 0.511, 0.520, 0.517 and 0.503 with the PTM modifications. SignificanceThe identified deleterious SNPs (D39Y and S51Y) fall in the functional and conserved domain of GAPDH. In addition, the existence of PTMs within the IDR region of the GAPDH may contribute to its enhanced glycolytic activity in LUAD. The results of our study provide potential background deleterious mutants the pathological aspect of GAPDH in LUAD progression.

Mechanism of Shashen-Maidong herb pair in treating hepatocellular carcinoma using network pharmacology and experimental validation

Ethnopharmacological relevanceHepatocellular carcinoma (HCC) is among the most prevalent malignant tumors globally and represents a significant public health issue worldwide. Immune cell dysfunction is the crucial factor for the formation of immunosuppression microenvironment of HCC. Glehnia littoralis (A.Gray) F.Schmidt ex Miq. (Shashen) and Ophiopogon japonicus (Thunb.) Ker Gawl. (Maidong) are classic herb pair in traditional Chinese medicine (TCM) of nourishing Yin, and is widely applied in the treatment of HCC and possesses multiple immunomodulatory functions. However, the role of the the Shashen-Maidong herb pair (SS-MD) for the management of HCC and the potential mechanisms has not been explicated. Aim of the studyThe purpose of the research is to investigate the potential mechanism of the SS-MD herb pair for the management of HCC. Materials and methodsThe known components of the SS-MD herb pair were preliminarily identified using UPLC-Q-Orbitrap-MS/MS. The active ingredients of SS-MD herb pair in treating HCC were screened by constructing herb-component-target network, and the key therapeutic targets were explored by constructing a protein-protein interaction (PPI) network. The binding affinity of the key targets and components were validated through molecular docking and molecular dynamics simulations. GO biological function and KEGG pathway analyses were operated to elucidate the potential mechanisms of the SS-MD herb pair for the management of HCC. And the mechanism was verified in the tumor bearing mice model and cell co-culture experiments. ResultsNetwork pharmacology prediction revealed 39 active components and 138 targets of the SS-MD herb pair for the treatment of HCC. KEGG analysis mainly focused on Notch signaling pathway and Apoptosis signaling pathway. The targets were enriched in biological functions of lymphocyte effector function and lymphocyte apoptosis. In vivo and in vitro experiments proved that the SS-MD herb pair can improve the proportion of CD8+T cells in the HCC immune microenvironment, regulate its subgroup distribution. SS-MD herb pair promoted CD8+T cells to secrete IL-2, TNF-α, IFN-γ, Granzyme B and Perforin, and inhibited apoptosis by regulating Notch signaling pathway. ConclusionsThis study identified the key components, targets, and signaling pathways of the SS-MD herb pair, confirm that SS-MD herb pair play an immunomodulatory role in treating HCC, provides theoretical support for the collaborative treatment of HCC with TCM.

Exploring the anti-diabetic activity of 2,6-diamino-4-chloropyrimidinium-hydrogen oxalate conjugates: Synthesis, crystal structure, quantum computational, drug-likeness, molecular docking and dynamics simulation

Inhibiting carbohydrate-hydrolyzing enzyme has been considered as an effective approach for controlling starch digestion and postprandial blood glucose level. The aim of this study, the salt molecule was prepared to identify potentially effective compound against diabetic activity and discover the inhibitory mechanism of the targeted enzyme, which is determined by In-silico techniques. And also perform the quantum chemical calculation to provide insights about the internal motions of the molecule at the atomic level. The 2,6-diamino-4-chloropyrimidinium-hydrogen oxalate (C4H6ClN4+. C2HO4-) was newly synthesized molecule, which is detailly discussed in this present work. The title compound has been confirmed by single-crystal X-ray diffraction studies, and this structure was refined by the least-square refinement method. The crystal compound exhibited the P-1 space group (centrosymmetric) and the following unit cell parameters: a = 5.5778(6)Å, b = 9.6687(10)Å, c = 9.9144(10)Å, α = 116.342(1) °, β = 92.610(1) °, γ = 106.370(1) °, Z = 2. The molecular structure is stabilized by the networks of N–H···O, O–H···O, C–H···O, and N–H···N hydrogen bond interactions. The Hirshfeld surface (HS) analysis and fingerprint plots revealed strong intermolecular interaction between the molecules. The structural optimization, frontier molecular orbital (FMO), molecular reactivity, molecular electrostatic potential (MEP), and mulliken atomic charges were generated by the density functional theory (DFT) calculated at B3LYP/6-311G++ (d,p) theory level. Drug-likeness and physicochemical properties were predicted. The molecular docking analysis was showed a binding energy of −8.96 kcal/mol within the active site of alpha-amylase, which is responsible for anti-diabetic activity. The protein-ligand complex stability was verified using molecular dynamics studies with 100 ns.

Molecular docking and dynamics simulation analysis of PDE5 inhibitor candidates for erectile dysfunction treatment.

Molecular docking studies were conducted to assess the binding affinities of five potential inhibitor candidates [PDB (Protein Data Bank) ID: 6L6E] against Phosphodiesterase 5 (PDE5), with Sildenafil used as the reference compound. The aim of this study is to reveal the potential inhibitory role of plant-derived compounds compared to Sildenafil, a PDE5 inhibitor. Autodock Vina v. 1.2.5 software was used to dock the protein and each ligand individually. Molecular dynamics simulations assessed the binding affinity of two compounds to the Phosphodiesterase 5A1 (PDE5 A1) enzyme and were carried out using GROMACS 2022.2 RESULTS: Boesenbergin A exhibited the highest affinity at -8.8 kcal/mol, followed by Ginkolide B at -8.5 kcal/mol, Sildenafil at -8.1 kcal/mol, Montanol at -7.8 kcal/mol, Beta-sitosterol at -7.1 kcal/mol, and Eugenol acetate at -6.9 kcal/mol, ranked in descending order. As a result of molecular docking studies, molecular dynamic simulations were performed for Boesenbergin A, which has the highest affinity, and Sildenafil, which is the standard molecule. Among the two ligands tested, Boesenbergin A exhibited superior binding affinity, surpassing even the standard molecule, Sildenafil. This suggests their potential for modulating enzyme activity and potential relevance in erectile dysfunction treatment.

Virtual Screening of Flavonoids against Plasmodium vivax Duffy Binding Protein Utilizing Molecular Docking and Molecular Dynamic Simulation.

Plasmodium vivax (P. vivax) is one of the highly prevalent human malaria parasites. Due to the presence of extravascular reservoirs, P. vivax is extremely challenging to manage and eradicate. Traditionally, flavonoids have been widely used to combat various diseases. Recently, biflavonoids were discovered to be effective against Plasmodium falciparum. In this study, in silico approaches were utilized to inhibit Duffy binding protein (DBP), responsible for Plasmodium invasion into red blood cells (RBC). The interaction of flavonoid molecules with the Duffy antigen receptor for chemokines (DARC) binding site of DBP was investigated using a molecular docking approach. Furthermore, molecular dynamic simulation studies were carried out to study the stability of top-docked complexes. The results showed the effectiveness of flavonoids, such as daidzein, genistein, kaempferol, and quercetin, in the DBP binding site. These flavonoids were found to bind in the active region of DBP. Furthermore, the stability of these four ligands was maintained throughout the 50 ns simulation, maintaining stable hydrogen bond formation with the active site residues of DBP. The present study suggests that flavonoids might be good candidates and novel agents against DBP-mediated RBC invasion of P. vivax and can be further analyzed in in vitro studies.

Identification of Peptidoglycan Glycosyltransferase FtsI as a Potential Drug Target against Salmonella Enteritidis and Salmonella Typhimurium Serovars Through Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Approaches.

Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium are among the main causative agents of nontyphoidal Salmonella infections, imposing a significant global health burden. The emergence of antibiotic resistance in these pathogens underscores the need for innovative therapeutic strategies. To identify proteins as potential drug targets against Salmonella Enteritidis and Salmonella Typhimurium serovars using In silico approaches. In this study, a subtractive genomics approach was employed to identify potential drug targets. The whole proteome of Salmonella enteritidis PT4 and Salmonella typhimurium (D23580), containing 393 and 478 proteins, respectively, was analyzed through subtractive genomics to identify human homologous proteins of the pathogen and also the proteins linked to shared metabolic pathways of pathogen and its host. Subsequent analysis revealed 19 common essential proteins shared by both strains. To ensure hostspecificity, we identified 10 non-homologous proteins absent in humans. Among these proteins, peptidoglycan glycosyltransferase FtsI was pivotal, participating in pathogen-specific pathways and making it a promising drug target. Molecular docking highlighted two potential compounds, Balsamenonon A and 3,3',4',7-Tetrahydroxyflavylium, with strong binding affinities with FtsI. A 100 ns molecular dynamics simulation having 10,000 frames substantiated the strong binding affinity and demonstrated the enduring stability of the predicted compounds at the docked site. The findings in this study provide the foundation for drug development strategies against Salmonella infections, which can contribute to the prospective development of natural and cost-effective drugs targeting Salmonella Enteritidis and Salmonella Typhimurium.